Dental caries (tooth decay) is one of the most prevalent and costly infectious diseases in the United States. The oral cavity harbors a complex microbial community consisting of over 600 different non-harmful/commensal microbial species together with a limited number of pathogenic bacteria, including the major etiological agent of dental caries, Streptococcus mutans, which ferments dietary sugars to produce enamel-damaging organic acids. The eradication of S. mutans and the control of re-infection/re-growth are crucial to combat caries pathogenesis and the high-costs associated with caries repair. Once established in the oral microbial community, S. mutans can persist despite diligent dental hygiene practices. The current antimicrobial strategies used to treat dental caries consist primarily of mechanical removal of dental plaque or a generalized killing of oral bacteria with broad-spectrum antimicrobial compounds. These "remove all, kill-all" approaches have shown limited efficacy, since a "cleaned" tooth surface provides an equal opportunity for commensal as well as pathogenic bacteria to re-colonize in the non-sterile environment of the oral cavity. S. mutans can dominate the dental plaque after such treatment and start another cycle of cariogenesis. In this study, we propose a novel, innovative approach to address this problem. Our working hypothesis is that by selectively killing or inhibiting S. mutans within a pathogenic dental plaque, we can establish a non-pathologic, commensal microbial community. This "healthy plaque" will then serve as an effective barrier to prevent subsequent S. mutans re-colonization, leading to a sustained anti-caries effect. To achieve this goal, we propose to create a novel set of molecules for specifically-targeted photodynamic therapy that will exhibit S. mutans-selective antimicrobial activity upon activation with a blue light source common to dental practices. In Phase I, we will obtain solid preliminary data to establish the technical/scientific merit of this novel approach. The specific goals are: "Aim 1. We have generated a number of small peptides with specific binding to S. mutans. We will conjugate these peptides to molecules commonly utilized in photodynamic therapy to create a series of specifically-targeted photosensitizing compounds. These compounds will be tested for activity and S. mutans specificity against monoculture S. mutans biofilms and defined limited oral communities, in vitro. "Aim 2. The most active and selective conjugates will be further tested for targeted S. mutans killing within multispecies saliva-derived biofilms. Furthermore, we will validate the working hypothesis by examining whether these novel molecules can trigger a community shift towards a "healthy plaque", which can prevent the future colonization or overgrowth of S. mutans. The successful execution of this research plan will lead to the development of a targeted antimicrobial therapy against S. mutans. Future Phase II studies will aim to optimize and formulate promising molecules into actual therapeutic products against oral microbial infections, and to determine safety in vitro and in vivo. Phase III studies will include human clinical trials to evaluate the safety and efficacy of these specifically-targeted photo-activated therapeutic agents. PUBLIC HEALTH RELEVANCE: The direct outcome of the proposed study will be the creation of novel, light-activated, S. mutans-targeted antimicrobial therapeutics for the treatment of dental caries, a prevalent and costly disease that has remained entrenched in the United States as well as worldwide. A dramatic reduction in the human suffering and high costs associated with caries treatment could result from the utilization of this therapeutics. Additionally, targeted photosensitizers will be inexpensive to manufacture at any scale and can be activated by blue dental curing lights common to general and specialized dental practices. Successful implementation of this technology will provide long-lasting antimicrobial effects, which is particularly suitable for underserved populations. The goal of this study is consistent with the mission of the SBIR program. It will encourage and support innovative research from a small business on the etiology, pathogenesis, prevention, diagnosis, and treatment of oral, craniofacial, and dental diseases and disorders.